Highlights from Recent Cancer Literature
Journal: Cancer Research (2011)

Mathieu J, Zhang Z, Zhou W, Wang AJ, Heddleston JM, Pinna CMA, et al. HIF induces human embryonic stem cell markers in cancer cells. Cancer Res 2011;71:4640–52.Hypoxia enhances malignancy, as tumors with significant hypoxic microenvironments correlate with tumor aggressiveness and poor clinical outcome. The accepted explanation for this is that the hypoxia-inducible transcription factor (HIF) induces mRNA expression of multiple regulators of angiogenesis, including VEGF, as well as inflammatory cytokines and other mediators that blunt productive antitumor CD8 T-cell responses. Mathieu and colleagues add a new dimension to HIF functionality and provide new insights that enhance our understanding of cancer stem–like cells. The authors demonstrate that hypoxia, via HIF, can induce expression of markers commonly expressed on human embryonic stem cells in human carcinoma cell lines. In total, 11 different cell lines, derived from 8 different common malignancies as well as primary malignant cells isolated from a glioma, showed a similar response: Hypoxia-induced expression of OCT4, NANOG, MYC, SOX2, KLF4, and MiR-302 by malignant cells led to subsequent generation of highly tumorigenic colonies. The hypoxia-induced gene expression signature was also shared by 9 human embryonic stem cell lines. In primary prostate tumor biopsies, the authors found a correlation between NANOG, OCT4, and HIF-1α–positive tumor regions, and NANOG and OCT4 positivity increased with aggressiveness as measured by Gleason scoring. These data may explain why some cancers are enriched with more cancer stem–like cells than others, and why the stem-like state is more dynamic than previously thought. The ability of hypoxia to induce or foster a tumor environment favoring dedifferentiation of malignant cells adds to the growing body of evidence suggesting that anticancer strategies neutralizing tumor hypoxia could improve clinical outcomes. Moreover, these results may also explain in part why tumors that progress following angiogenesis inhibitor therapy tend to acquire enhanced growth properties and histopathologic properties of increased aggressiveness.Jirawatnotai S, Hu Y, Michowski W, Elias JE, Becks L, Bienvenu F, et al. A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. Nature 2011;474:230–4.Cyclin D1 is among the most commonly amplified genes in human cancer. Cyclins are allosteric regulators of cyclin-dependent kinases (CDK), with cyclin D1 activating CDK4 and CDK6, leading to phosphorylation and inactivation of the retinoblastoma (RB) tumor suppressor and promoting S-phase entry. Jirawatnotai and colleagues conducted a proteomic screen to identify cyclin D1–interacting proteins in 4 different cancer-derived cell lines in which cyclin D1 was amplified or activated. These studies identified an interaction network involving cyclin D1 and RAD51, a key recombinase involved in DNA repair. The authors went on to show that cyclin D1 protein binds to RAD51 protein, and that cyclin D1 is recruited to DNA damage as part of a complex that also includes the DNA repair protein BRCA2. Knockdown of cyclin D1 in RB mutant cell lines sensitized RB mutant lines to gamma radiation. These data demonstrate a role for cyclin D1 independent from its role in cell-cycle regulation, and further suggest a role for small-molecule inhibitors of cyclin D1 in the treatment of both RB wild-type and RB-mutant cancers.Fernandez AF, Assenov Y, Martin-Subero J, Balint B, Siebert R, Taniguchi H, et al. A DNA methylation fingerprint of 1,628 human samples. Genome Res 2011 May 25. [Epub ahead of print].CpG dinucleotides occur in a majority of mammalian promoter sequences, forming CpG islands (CGI). Methylation of CGIs is associated with silencing of promoter activity and shows aberrant regulation in cancer. CGIs may also be methylated within and outside of genes (intragenic and intergenic methylation of CGIs) in which the functional role of DNA methylation is less clear. Fernandez and colleagues analyzed DNA samples from a large number of tissues (424 normals; 1,054 tumors; and 151 dementia, cardiovascular, and autoimmune), observing a progressive gain of methylation at promoters and loss of methylation in nonpromoter CGIs. Interestingly, this group could use methylation patterns to identify the putative source in cancers for which the primary tumor is unknown, a finding that may have therapeutic importance.Benitiz A, Yates TJ, Lopez LE, Cerwinka WH, Bakkar A, Lokeshwar VB. Targeting hyaluronidase for cancer therapy: antitumor activity of sulfated hyaluronic acid in prostate cancer cells. Cancer Res 2011; 71:4085–95.Tumor growth and metastasis are facilitated by tumor-associated hyaluronic acid (HA) and the hyaluronidase (HAase) system. HYAL-1, a tumor-derived HAase, is expressed in malignant cells and tissues and promotes tumor growth, invasion, and angiogenesis in prostate and bladder cancer models. Although HYAL-1 expression appears to be a biochemical determinant of cancer growth and progression, targeting this molecule for cancer therapy has not been previously investigated. Moreover, the biological activity of sulfated HA (sHA) that also inhibits HAase has not been examined. Benetiz and colleagues provide evidence that sHA is an effective inhibitor of prostate carcinoma cell proliferation, motility, and invasion. sHA induces caspase 8–dependent apoptosis and correlates with downregulation of Bcl-2 and phosphorylation of Bad in a series of prostate carcinoma cell lines. Akt signaling, including androgen receptor (AR) phosphorylation, AR activity, NF-κb activation, and VEGF expression, was also found to be inhibited by sHA. In an LNCaP-AI prostate cancer animal model, sHA strongly inhibited tumor growth, decreasing tumor angiogenesis and increasing apoptotic index, without causing weight loss or apparent serum-organ toxicity. These intriguing results suggest that the tumor-associated HA-HAase system may provide a new target for therapeutic intervention in prostate cancer growth and progression.Poage GM, Houseman EA, Christensen BC, Butler RA, Avissar-Whiting M, McClean MD, et al. Global hypomethylation identifies loci targeted for hypermethylation in head and neck cancer. Clin Cancer Res 2011;17:3579–89.Head and neck squamous cell carcinoma (HNSCC) is common throughout the world, representing the sixth most common malignancy overall. A number of etiologic risk factors for HNSCC have been identified, including alcohol and tobacco use and infection with human papillomavirus type 16. In these cancers, a number of epigenetic changes have been identified, including hypermethylation of promoters that are associated with known tumor suppressor genes CDKN2A, CDH1, DAPK1, RASSF1, and MGMT. Multiple studies have highlighted unique epigenomic alterations involved in driving the carcinogenic process; however, additional studies are required to understand the epigenetic basis of this disease. In the present study, global methylation was measured using high-throughput methylation assays in 138 fresh-frozen tumor specimens from head and neck sites. With the use of these specific assay systems, frequent global hypomethylation and hypermethylation of specific sets of target genes, including EVI2A, IFRD1, KLHL6, and PTPRCAP, were found in patients with HNSCC. These data indicate that global hypomethylation and gene-specific hypermethylation processes are sequentially orchestrated in disease development. Identification and establishment of a panel of commonly hypermethylated genes in HNSCC, and their association with HNSCC development and progression, could provide an ideal framework to develop suitable management strategies for HNSCC.Hood JL, Roman SS, Wickline SA. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res 2011;71:3792–801.Metastasis is a complex process involving intrinsic changes in evolving tumor cells and their interactions with the microenvironment. In order to colonize at new sites in the body, the conditions for deposition and growth at those distant sites must be optimal. Based on the “seed and soil” hypothesis, metastatic cancer cells (or cancer stem cells) serve as seeds and the microenvironment provides the soil for the colonization. In this context, the sites for metastasis may be modified, preparing them for this critical component of the cancer process prior to actual metastasis. In the context of metastatic melanoma, metastasis involves lymphatic dissemination, although the exact role of lymph nodes in potentiating this process is poorly defined. Tumors communicate signals to local and remote cells and tissues through exosomes, which are natural biological nanovesicles. The exosomes of melanoma can promote a proangiogenic signaling cascade that can remodel tissue matrices. In the present study Hood and colleagues show that melanoma exosomes can condition lymph nodes facilitating metastasis. By homing to sentinel lymph nodes, melanoma exosomes elicit synchronized molecular events that affect melanoma cell recruitment, extracellular matrix deposition, and vascular proliferation in the lymph nodes. These studies provide new and interesting perspectives on the role of melanoma exosomes in facilitating the metastatic process.Li LY, Chen H, Hsieh YH, Wang YN, Chu HJ, Chen YH, et al. Nuclear ErbB-2 enhances translation and cell growth by activating transcription of rRNA genes. Cancer Res 2011;71:4269–79.The rate-limiting step for translation/protein synthesis and cell growth involves rRNA production by RNA polymerase-1 (RNA Pol I). Increased protein synthesis and cell growth facilitated by rRNA expression can enhance tumor development and has been reported to be elevated in a spectrum of human cancers. Moreover, many oncoproteins and tumor suppressor proteins can affect tumorigenesis by regulating various components of the translation machinery. In these contexts, specific components of the translation apparatus may provide potential targets for intervention in tumor growth and development. Many human tumors overexpress ErbB2 growth factor receptor, which has been detected in the nucleus, where their role is not well defined. Li and colleagues document a unique function of nuclear ErbB2 that involves enhanced rRNA gene transcription by RNA Pol I. Their data suggest the existence of a physical interaction between ErbB2, β-actin, and RNA Pol I at sites in nucleoli. Chromatin immunoprecipitation assays showed that ErbB2 enhanced binding of RNA Pol I to rDNA. These interesting findings support the argument that ErbB2 can function as a regulator of rRNA synthesis and cellular translation, potentially playing a role in tumor etiology and progression.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.